Pain Reliever Composition

ABSTRACT

An inventive composition including an amount of sugar or sugar alcohol, an amount of alkalizing agent, and an amount of vehicle; whereby the inventive composition is formulated for transdermal administration to alleviate one or more disorder symptoms, for example neurogenic pain, or to treat one or more disorders, for example neurogenic inflammation.

This United States patent application is a continuation-in-part of U.S.patent application Ser. No. 14/294,034, filed Jun. 2, 2014, which is acontinuation of U.S. patent application Ser. No. 13/479,998, filed May24, 2012, which is a continuation-in-part of U.S. patent applicationSer. No. 13/417,053, filed Mar. 9, 2012, which is a continuation-in-partof U.S. patent application Ser. No. 13/295,010, filed Nov. 11, 2011,each hereby incorporated by reference herein.

I. BACKGROUND OF THE INVENTION

Pain is one of the most frequent symptoms for which patients seekmedical intervention. Pain may be classified as acute or chronic. Acutepain may be generally associated with excessive noxious stimulusresulting in a severe distressful sensation whereas chronic pain may beassociated with physiological changes resulting from tissue or nerveinjury leading to hyperalgesia, an increased amount of pain associatedwith a mild noxious stimulus, or allodynia, a pain induced by anon-noxious stimulus.

Neurogenic pain is a neurological disorder caused by insult toperipheral nerves, resulting in chronic pain and varying combinations ofsensory symptoms, including paresthesia, loss of sensation, and evenmotor weakness. Neurogenic pain may be long-lasting, and may developdays or month following the injury. Often, this type of chronic pain maybe observed in diseases affecting the peripheral nervous system, such asnerve compression syndromes, cutaneous sensory neuropathies andpolyneuropathies (of which diabetic neuropathy may be the mostwell-known).

Amongst the various types of chronic pain, understanding and managementof neurogenic pain remains a considerably challenging task forresearchers and clinicians. Despite the rapid development ofneuroscience and the discovery of new pharmaceutical compounds, a needcontinues to exist for an effective treatment based on a basicunderstanding of the contributing molecular mechanisms of neurogenicpain.

Neurogenic pain involves alterations in the function of both theperipheral and central nervous system, postulated to be caused bychanges in mechano-insensitive peptidergic nociceptors referred to as“silent” or “sleeping” nociceptors, which are chemo-sensitive andrespond to noxious chemicals typically released in response to tissue ornerve trauma. Once sensitized, the phenotype of the nociceptors can bealtered, whereby the formerly “silent” or “sleeping” nociceptors become“polymodal” or “awake” nociceptors (C fibers), which release significantamounts of pro-inflammatory neuropeptides, such as calcitoningene-related peptide (CGRP) or substance P (SP), initiating neurogenicinflammation in combination with enhancing action potentials, therebyresulting in increased nociception.

Following nerve injury, increased excitability and sensitivity isobserved in the cell body of the injured dorsal root ganglia neurons andneighboring intact afferent neurons. This enhanced stimulation involvingthe primary afferent neurons is defined as peripheral sensitization,which is mediated by increased expression of the transient receptorpotential (TRP) family of non-specific cation channels, includingtransient receptor potential cation channel subfamily V member 1(TRPV1), which is expressed in C fibers and Aδ fibers. Another mechanismleading to peripheral sensitization includes the accumulation ofvoltage-gated sodium channels at the site of the injured nerve and atthe dorsal root ganglion, resulting in abnormal ectopic excitability ofafferent neurons. These changes may be perceived as spontaneous positivesensations, such as paresthesia (a sensation of tingling, burning,pricking, or numbness of skin) or dysthesia (an unpleasant, abnormalsense of touch).

Central sensitization, defined as the activation of second ordernociceptive neurons in the dorsal horn of the spinal cord by peripheralnerve damage, results from the release of glutamate, SP, or othertransmitters or cytokines, such as adenosine-5′-triphosphate (ATP),chemokine (C-C motif) ligand 2 (CCL2), or interferon gamma (INFγ), fromthe central terminals of primary nociceptive afferents in the dorsalhorn. The overall effect of these changes may be prolonged excitabilityof the spinal cord neurons (long-term potentiation).

Further contributing factors to the development of neurogenic paininclude the involvement of spinal cord microglia and astrocytes inenhancing pain, whereby ATP-activated microglial P2X4 and P2X7 receptorsstimulate the p38 mitogen-activated protein kinases (p38-MAPK)signalling cascade, resulting in release of substances such asbrain-derived neurotrophic factor (BNDF), down-regulation ofpotassium/chloride cotransporters, and diminished inhibitoryneurotransmission (GABAergic inhibition).

Additionally, following an injury, various inflammatory substances suchas histamines, prostaglandins, or cytokines, may be released frominflammatory cells which have migrated through the blood to the site ofthe injured tissue. When the injury results in nerve damage, theperipheral terminals of sensory neurons may be activated, resulting ininflammation characterized by the release of neuropeptides, such asCGRP, SP, or calcitonin, from the C fiber terminal, which can lead tovasodilation, edema, or pain. As such, neurogenic inflammation plays anintegral role in the pathophysiology of neurogenic pain.

Successful treatment of neurogenic pain requires direct targeting of thereceptors and transmitters involved. Conventional therapeutic strategiesaim to reduce neuron excitability through alterations in ion channelactivity, which may be targeted by compounds such as gabapentin orlidocaine, or modulate central neurotransmission, which may be targetedby compounds such as opioids or tricyclic antidepressants. Despiteconsistent efficacy observed in randomized trials and meta-analyses, theuse of these agents may be limited due to debilitating side effects,such as sedation, somnolence, dry mouth, urinary retention, erythema,ataxia, or the like, or combinations thereof. Moreover, patients usingthese compounds must be closely monitored and dose tapering may berequired to prevent withdrawal symptoms. Accordingly, a need exists fora novel alternative characterized by maximal therapeutic efficacy,minimal toxicity, and low incidence of side effects.

II. SUMMARY OF THE INVENTION

A broad object of a particular embodiment of the invention can be toprovide an inventive composition including an amount of sugar or sugaralcohol, an amount of alkalizing agent, and an amount of vehicle;whereby the inventive composition is formulated for transdermaladministration.

Another broad object of a particular embodiment of the invention can beto provide a method of using the inventive composition, the methodincluding transdermally administering the inventive composition toalleviate one or more disorder symptoms, for example neurogenic pain, orto treat one or more disorders, for example neurogenic inflammation.

Another broad object of a particular embodiment of the invention can beto provide a method of producing an inventive composition, the methodincluding combining an amount of sugar or sugar alcohol, an amount ofalkalizing agent, and an amount of vehicle; and formulating theinventive composition for transdermal administration.

Naturally, further objects of the invention are disclosed throughoutother areas of the specification, drawings, and claims.

III. DETAILED DESCRIPTION OF THE INVENTION

A method of using a particular embodiment of the inventive compositionincluding an amount of sugar or sugar alcohol, an amount of alkalizingagent, and an amount of vehicle, whereby the inventive composition isformulated for transdermal administration, can include administering theinventive composition to an external surface of a body to alleviate oneor more disorder symptoms, for example neurogenic pain, or to treat oneor more disorders, for example neurogenic inflammation.

The term “sugar” for the purposes of this invention means anycarbohydrate or saccharide, including monosaccharides, disaccharides,oligosaccharides, or polysaccharides.

The term “sugar alcohol” for the purposes of this invention means anypolyol (or polyhydric alcohol) derived from a sugar. The polyol cantypically include an alcohol group (CH₂OH) in place of an aldehyde group(CHO) of the parent sugar.

The term “alkalizing agent” for the purposes of this invention means anagent capable of adjusting a pH from a lesser alkalinity toward agreater alkalinity.

The term “symptom” for the purposes of this invention means anydiscomfort or combination of discomforts associated with a disorder.Without limiting the breadth of the foregoing, symptoms can include:pain, dyesthesia, paresthesia, sensory loss, allodynia, hyperpathia,reduced range-of-motion, motor weakness, or the like, or combinationsthereof.

The term “disorder” for the purposes of this invention means a physicalor mental condition which may not be normal or healthy. Without limitingthe breadth of the foregoing, a disorder can include: known compressivemononeuropathies (such as carpal tunnel syndrome, cubital tunnelsyndrome, or tarsal tunnel syndrome), regional pain conditions (such assub-occipital neuralgia, facial neuralgias, headache, neck pain, or backpain), acute joint injury which may include a component of nerveinflammation (such as ankle sprain or strain), tendinopathiespotentially promoted or aggravated by concomitant neurogenic components(such as Achilles tendonosis, lateral epicondylosis, or medialepicondylosis), or isolated inflammation of any one or more peripheralnerves (such as cranial and upper cervical nerve branch derivatives ofthe face and cranium).

The term “topical administration or “transdermal administration” for thepurposes of this invention means the administration of one or morecomponents of a composition or compound to and typically, but notnecessarily, through the epidermis on any external surface of a body. Asto particular embodiments, topical administration or transdermaladministration can mean the administration of one or more components ofa composition or compound to the epidermis on any external surface of abody and typically, but not necessarily, through the dermis. Followingtopical administration or transdermal administration, one or morecomponents of the composition or compound may or may not be systemicallybioavailable.

Where trade names or trademarks are utilized herein, whether in Table 1through Table 7, or any table, figure, or portion of the description,the trade name material or the trademark material is understood to havethe chemicals or ingredients in the amounts or combinations as describedbelow. The trade name material or trademark material or a substantiallyequivalent product or combination of chemicals or ingredients can beutilized in embodiments of the inventive composition. It is furtherunderstood that where a trade name material or trademark material isutilized in a table or figure that substantially equivalent chemicals oringredients in the amounts and combinations as indicated below can beutilized in substitution of the trade name material or trademarkmaterial. A person of ordinary skill in the art can convert the weightpercentages shown in the tables or figures to determine the amount ofeach chemical or ingredient to mix when the equivalent of the trade namematerial or trademark material is prepared.

Where the constituents of a particular trade name material or trademarkmaterial have been set out a first time in the description below, eachapplies to the subsequent uses of the trade name material or trademarkmaterial in the description, tables and figures.

Now referring primarily to Table 1, embodiments of the inventivecomposition can include formulations having raw materials admixed in theexemplary weight percentages (“Weight Percent”) shown in column two ofTable 1. Numerous embodiments of the inventive composition can beprepared by altering the weight percentages of the raw materials withinthe range weight percentages (“Range Weight Percent”) shown in columnthree of Table 1 with an amount of vehicle making up the balance.

TABLE 1 Range Weight Raw Material Weight Percent Percent Sugar or SugarAlcohol 20 2 to 30 Alkalizing Agent 5 0.1 to 15 Vehicle 75 55 to 97.9

As to particular embodiments, the sugar can include a monosaccharide,such as ribose (CAS No: 50-69-1), xylose (CAS No: 58-86-6), fructose(CAS No: 57-48-7), dextrose (glucose) (CAS No: 50-99-7), galactose (CASNo: 59-23-4), mannose (CAS No: 31103-86-3), sorbose (CAS No: 87-79-6),or the like, or combinations thereof, all of which can be obtained fromSigma-Aldrich, 3050 Spruce Street, St. Louis, Mo., USA. As to otherparticular embodiments, the sugar can include a disaccharide, such assucrose (CAS No: 57-50-1), maltose (CAS No: 69-79-4), lactose (CAS No:63-42-3), lactulose (CAS No: 4618-18-2), trehalose (CAS No: 99-20-7),cellobiose (CAS No: 528-50-7), or the like, or combinations thereof, allof which can be obtained from Sigma-Aldrich, 3050 Spruce Street, St.Louis, Mo., USA.

The sugar can be generally included in an amount of about 2% to about30% by weight of the inventive composition; however, greater or lesserweight percents of the sugar can be included depending on the disordersymptom to be alleviated or the disorder to be treated.

As to particular embodiments, the amount of sugar included in theinventive composition can be selected from the group including orconsisting of: between about 5% to about 30% by weight of the inventivecomposition; between about 10% to about 30% by weight of the inventivecomposition; between about 15% to about 30% by weight of the inventivecomposition; and between about 20% to about 30% by weight of theinventive composition. As to the particular embodiment of the inventivecomposition shown in Table 1, the amount of sugar, for example dextrose,included can be about 20% by weight of the inventive composition.

The amount of sugar included in the inventive composition can beinfluenced by factors such as user anatomy, physiology, or biochemistryof the epidermis or underlying tissue; disorder symptom targeted foralleviation; disorder targeted for treatment; observable effect(s) ofthe application of the inventive composition; or the like; orcombinations thereof; but not so much as to cause discomfort to the useror irritation to the epidermis or underlying tissue.

The sugar alcohol can include a polyol derived from a monosaccharide ora disaccharide, including glycerol (CAS No: 56-81-5), erythritol (CASNo: 10030-58-7), threitol (CAS No: 2418-52-2), arabitol (CAS No:7643-75-6), xylitol (CAS No: 87-99-0), adonitol (CAS No: 488-81-3),mannitol (CAS No: 69-65-8), sorbitol (CAS No: 50-70-4), dulcitol (CASNo: 608-66-2), fucitol (CAS No: 13074-06-1), iditol (CAS No: 488-45-9),inositol (CAS No: 87-89-8), volemitol (CAS No: 30635-52-0), isomalt (CASNo: 64519-82-0), maltitol (CAS No: 585-88-6), lactitol (CAS No:585-86-4), maltotriitol (CAS No: 32860-62-1), or the like, orcombinations thereof, all of which can be obtained from Sigma-Aldrich,3050 Spruce Street, St. Louis, Mo., USA.

The sugar alcohol can be generally included in an amount of about 2% toabout 30% by weight of the inventive composition; however, greater orlesser weight percents of the sugar alcohol can be included depending onthe disorder symptom to be alleviated or the disorder to be treated.

As to particular embodiments, the amount of sugar alcohol included inthe inventive composition can be selected from the group including orconsisting of: between about 5% to about 30% by weight of the inventivecomposition; between about 10% to about 30% by weight of the inventivecomposition; between about 15% to about 30% by weight of the inventivecomposition; and between about 20% to about 30% by weight of theinventive composition. As to the particular embodiment of the inventivecomposition shown in Table 1, the amount of sugar alcohol, for examplemannitol, included can be about 20% by weight of the inventivecomposition.

The amount of sugar alcohol included in the inventive composition can beinfluenced by factors such as user anatomy, physiology, or biochemistryof the epidermis or underlying tissue; disorder symptom targeted foralleviation; disorder targeted for treatment; observable effect(s) ofthe application of the inventive composition; or the like; orcombinations thereof; but not so much as to cause discomfort to the useror irritation to the epidermis or underlying tissue.

The alkalizing agent can include any agent capable of adjusting a pHfrom a lesser alkalinity toward a greater alkalinity, such as sodiumbicarbonate (CAS No: 144-55-8), potassium citrate (CAS No: 866-84-2),calcium carbonate (CAS No: 471-34-1), calcium acetate (CAS No: 62-54-4),or the like, or combinations thereof, all of which can be obtained fromSigma-Aldrich, 3050 Spruce Street, St. Louis, Mo., USA.

As to particular embodiments, the alkalizing agent can include a salt.As to particular embodiments, the salt can include a monovalent cation,a divalent cation, or a trivalent cation, including but not limited tosodium, calcium, potassium, zinc, iron, magnesium, or the like, orcombinations thereof. As to other particular embodiments, the salt caninclude an anion, including but not limited to chloride, acetate,ascorbate, bicarbonate, citrate, formate, fumarate, phosphate,succinate, borate, gluconate, lactate, malate, trimalate, panthothenate,thiocyanate, glycinate, sulphate, or the like, or combinations thereof.

As to particular embodiments, the salt can be selected from the groupincluding or consisting of: sodium chloride, sodium acetate, sodiumbicarbonate, sodium citrate, sodium phosphate, sodium dihydrogenphosphate, sodium hydrogen phosphate, sodium succinate, sodium borate,sodium gluconate, sodium citrate, sodium lactate, calcium citrate,calcium chloride, calcium pantothenate, calcium gluconate, calciumphosphate, potassium chloride, monopotassium phosphate, dipotassiumphosphate, tripotassium phosphate, potassium gluconate, magnesiumsulphate, magnesium chloride magnesium gluconate, magnesium acetate,.magnesium malate, magnesium glycinate, magnesium lactate, zincchloride, zinc sulphate and zinc acetate. Other exemplary salts may beformed from any combination of anions and cations listed above and mayinclude, anhydrous, hydrates, dehydrates, or the like, or combinationsthereof.

The alkalizing agent can be generally included in an amount of about0.1% to about 15% by weight of the inventive composition; however,greater or lesser weight percents of the alkalizing agent can beincluded depending on the disorder symptom to be alleviated or thedisorder to be treated. As to particular embodiments, the amount ofalkalizing agent included in the inventive composition can be in a rangeof between about 6.5% to about 15% by weight of the inventivecomposition.

As to particular embodiments, the amount of alkalizing agent included inthe inventive composition can be selected from the group including orconsisting of: between about 1% to about 15% by weight of the inventivecomposition, between about 1% to about 15% by weight of the inventivecomposition, between about 2.5% to about 15% by weight of the inventivecomposition, between about 5% to about 15% by weight of the inventivecomposition, between about 7.5% to about 15% by weight of the inventivecomposition, between about 10%/o to about 15% by weight of the inventivecomposition, and between about 12.5% to about 15% by weight of theinventive composition. As to the particular embodiment of the inventivecomposition shown in Table 1, the amount of alkalizing agent, forexample sodium bicarbonate, included can be about 5% by weight of theinventive composition.

The amount of alkalizing agent included in the inventive composition canbe influenced by factors such as user anatomy, physiology, orbiochemistry of the epidermis or underlying tissue; disorder symptomtargeted for alleviation; disorder targeted for treatment; observableeffect(s) of the application of the inventive composition; or the like;or combinations thereof; but not so much as to cause discomfort to theuser or irritation to the epidermis or underlying tissue.

The vehicle can include one or more excipients in which the sugar orsugar alcohol can be solubilized or suspended. As to particularembodiments, the excipient can render the inventive composition suitablefor topical application or transdermal application, whereby the vehiclecan facilitate the transdermal administration of a portion of the amountof sugar or sugar alcohol and a portion of the amount of alkalizingagent. As illustrative examples, the inventive composition including theamount of sugar or sugar alcohol, amount of alkalizing agent, and theamount of vehicle can take the form of lotion, cream, emulsion,ointment, gel, foam, paste, oil, lipid delivery system, spray, drops, orthe like, or combinations thereof.

The amount of vehicle included in the inventive composition can beinfluenced by factors such as user anatomy, physiology, or biochemistryof the epidermis or underlying tissue; disorder symptom targeted foralleviation; disorder targeted for treatment; observable effect(s) ofthe application of the inventive composition; or the like; orcombinations thereof; but not so much as to cause discomfort to the useror irritation to the epidermis or underlying tissue.

As to particular embodiments, the vehicle can include an emulsion base,which can have an oil phase. As illustrative examples, the oil phase caninclude vegetable oils, animal oils, mineral oils, silicone oils,synthetic oils, fatty acids, fatty alcohols, phospholipids, paraffinwaxes, or the like, or combinations thereof.

As to particular embodiments, the vehicle can further include one ormore solubilizing agents, such as cyclodextrins, surfactants, organicsolvents, alcohols, polysorbates, or the like, or combinations thereof.

As to particular embodiments, the vehicle can further include one ormore viscosity-increasing agents, such as microcrystalline cellulose,carboxymethylcellulose sodium, propylene glycol alginate, xanthan gum,polyacrylic acid, or the like, or combinations thereof.

As to particular embodiments, the vehicle can further include one ormore emulsifying or co-emulsifying agents, such as non-ionicsurfactants, polyethylene glycol esters, polyoxypropylene glycol ethers,sorbitan esters, ethoxylated sorbitan esters, poly esters, or the like,or combinations thereof.

As to particular embodiments, the vehicle can further include one ormore emulsion stabilizing agents, such as abietic acid, hydrogenatedlanolin alcohol, calcium myristate, hydroxyaluminium distearate,aluminum isostearate, aluminum stearate, 7, 8-didehydrocholesterol,aluminum magnesium hydroxide, stearic acid, lauryl alcohol, hydroxyethylcellulose, or the like, or combinations thereof.

As to particular embodiments, the vehicle can further include one ormore preservatives or preserving agents, such as sorbic acid, methylparaben, propyl paraben, benzoic acid, sodium benzoate cetrimide,phenoxyethanol, chlorphenisin, methylchloroisothiazolinone, or the like,or combinations thereof.

As to particular embodiments, the vehicle can further include one ormore penetration enhancers, such as alcohols, sulphoxides, azone,pyrrolidones, urea, disubstituted aminoacetates, glycols (for example,propylene glycol), surfactants, terpenes, terpenoids, fatty acids,esters, cyclodextrins, phospholipids, or the like, or combinationsthereof.

As to particular embodiments, the vehicle can further include water (CASNo: 7732-18-5), which can be filtered, de-ionized, distilled, or waterotherwise filtered or purified.

As an illustrative example, the vehicle can include Pentravan®, havingfatty acid alcohols, acids, esters, phospholipids, antioxidants,skin-feel enhancer, natural humectant, natural preservatives, nonionicemulsifiers, anionic emulsifiers, and buffer, which can be obtained fromFagron, 2400 Pilot Knob Road, St Paul, Minn. 55120, USA.

As an additional illustrative example, the vehicle can includeVersatile®, having waters, fatty acid esters, alcohols, paraffinicsilicone replacement, glidant, plant-derived emollient, vitamin E,nonionic emulsifiers, pro-liposomal phospholipids, and preservatives,which can be obtained from Fagron, 2400 Pilot Knob Road, St Paul, Minn.55120, USA.

As yet an additional illustrative example, the vehicle can includeVersaPro Cream Base™, which can be obtained from Medisca, 661 Route 3,Unit C, Plattsburgh, New York 12901, USA.

As to particular embodiments, the inventive composition can furtherinclude an amount of magnesium. As to particular embodiments, the amountof magnesium can be provided by magnesium chloride, magnesium sulfate,or the like, or combinations thereof.

As to particular embodiments, the inventive composition can furtherinclude an amount of Aesculus hippocastanum. As to particularembodiments, the amount of Aesculus hippocastanum can be in a range ofbetween about 0.25% to about 2% by weight of the inventive composition.As to particular embodiments, the amount of Aesculus hippocastanum caninclude an amount of aescin.

As to particular embodiments, the inventive composition can furtherinclude an amount of quercetin. As to particular embodiments, the amountof quercetin can be in a range of between about 0.1% to about 1% byweight of the inventive composition.

As to particular embodiments, the inventive composition can furtherinclude an amount of acetyl-L-carnitine. As to particular embodiments,the amount of acetyl-L-carnitine can be in a range of between about0.025% to about 3% by weight of the inventive composition.

As to particular embodiments, the inventive composition can furtherinclude an amount of zinc. As to particular embodiments, the amount ofzinc can be in a range of between about 0.025% to about 3% by weight ofthe inventive composition. As to particular embodiments, the amount ofzinc can be provided by zinc oxide, zinc sulfate, or the like, orcombinations thereof.

As to particular embodiments, the inventive composition can furtherinclude one or more colorants, fragrances, or the like, as persons ofordinary skill in the art would understand.

A method of using the inventive composition can include transdermallyadministering the inventive composition including an amount of sugar orsugar alcohol, an amount of alkalizing agent, and an amount of vehicle,whereby the inventive composition is formulated for transdermaladministration.

As to particular embodiments, the method of using the inventivecomposition can further include transdermally administering theinventive composition to an external surface of a body to alleviate oneor more disorder symptoms, for example to decrease neurogenic pain, orto treat one or more disorders, for example to decrease neurogenicinflammation.

As to particular embodiments, the method of using the inventivecomposition can further include transdermally administering theinventive composition along a nerve pathway of a nerve to decreaseneurogenic pain or to decrease neurogenic inflammation of the nerve.

As to particular embodiments, transdermally administering the inventivecomposition can alkalize a perineural environment proximate the nerve byadjusting a pH of the perineural environment from a lesser alkalinitytoward a greater alkalinity. As to particular embodiments, transdermallyadministering the inventive composition can decrease an amount ofhydrogen ions (H+) in the perineural environment proximate the nerve.

Research suggests an association between tissue acidity and neurogenicinflammation whereby hydrogen ions (H+) may prime the transient receptorpotential cation channel subfamily V member (TrpV1), thereby increasingneurogenic inflammation and corresponding neurogenic pain. Accordingly,decreasing the amount of hydrogen ions (H+) by adjusting the perineuralenvironment from a lesser alkalinity toward a greater alkalinity may bebeneficial for alleviating neurogenic pain or treating neurogenicinflammation.

As to particular embodiments, transdermally administering the inventivecomposition can decrease a viscosity of hyaluronic acid (also known ashyaluronan, hyaluronate, or HA), which is an anionic, nonsulfatedglycosaminoglycan widely distributed throughout connective, epithelial,and neural tissues. Particularly, hyaluronic acid can be found betweenfascial layers, acting as a lubricant to facilitate fascial glide. Asperipheral nerves, especially superficial sensory nerves, can typicallybe enveloped between fascial layers, decreasing the viscosity ofhyaluronic acid may decrease friction or mechanical irritation of thenerves by the fascia. Research suggests that adjusting the pH of aperineural environment from a lesser alkalinity toward a greateralkalinity may result in a conformational change in the hyaluronic acidmolecule resulting from a degradation of attraction forces betweenhyaluronic acid molecules, thereby increasing the flexibility of thehyaluronic acid polymer and correspondingly decreasing the viscosity ofhyaluronic acid.

As to particular embodiments, the method of using the inventivecomposition can further include transdermally administering theinventive composition formulated as a fluid, such as a lotion, cream,emulsion, ointment, gel, foam, paste, oil, lipid delivery system, spray,drops, or the like, or combinations thereof, to the external surface ofthe body to alleviate one or more disorder symptoms or to treat one ormore disorders.

As to particular embodiments, the method of using the inventivecomposition can further include administering one or more physical skinpenetration enhancement techniques before, during, or aftertransdermally administrating the inventive composition to the externalsurface of the body to alleviate one or more disorder symptoms or totreat one or more disorders. As illustrative examples, physical skinpenetration enhancement techniques can include phonophoresis,sonophoresis, iontophoresis, electroporation, radiofrequency-driven skinmicrochanneling, microneedles, massage, occlusion, heating, cooling, orthe like, or combinations thereof.

Now referring primarily to Table 2, which evidences the results of amethod of transdermally administering a particular embodiment of theinventive composition to twenty-six subjects (indicated in column 1 as“Subject Number”) who presented with various pain-related complaints(indicated in column 2 as “Primary Complaint”). As to this particularembodiment, the inventive composition included dextrose in an amount ofabout 20% by weight of the inventive composition, sodium bicarbonate inan amount of about 5% by weight of the inventive composition, andvehicle in an amount of about 75% by weight of the inventivecomposition.

TABLE 2 Percent Percent 5 Minutes Reduction 24 Hours Reduction SubjectPre-Admin Post-Admin in Pain Post-Admin in Pain Number Primary ComplaintPain Level Pain Level Level Pain Level Level 1 Post-surgical knee pain 40 100% 1 75% 2 Idiopathic knee pain 3 0 100% 1 67% 3 Radiating leg pain4 0 100% 1 75% 4 Post-surgical knee pain 8 0 100% 2 75% 5 Iliotibialband pain 2 0 100% 0 100%  6 Post-surgical hip pain 3 0 100% 0 100%  7Elbow pain 4 0 100% 0 100%  8 Severe low back & leg pain 8 0 100% 1 88%9 Neck pain & face paresthesia 8 0 100% 0 100%  10 Elbow/forearm pain 40 100% 1 75% 11 Shoulder pain 4 0 100% 1 75% 12 Post-surgical knee pain8 2  75% 2 75% 13 Post-surgical back pain 9 2  78% 2 78% 14 Plantarfasciitis 4 0 100% 1 75% 15 Plantar fasciitis 3 0 100% 1 67% 16Post-surgical knee pain 7 0 100% 1 86% 17 Acute lower back pain 6 0 100%0 100%  18 Severe low back & leg pain 10 2  80% 3 70% 19 Shoulder pain &restriction 4 0 100% 0 100%  20 Post-surgical shoulder pain 5 0 100% 0100%  21 Chronic shoulder pain 5 0 100% 0 100%  22 Acute upper back pain6 0 100% 0 100%  23 Acute shoulder pain 6 2  67% 2 67% 24 Chronicshoulder pain 9 1  89% 3 67% 25 Neck & shoulder pain 8 1  88% 3 63% 26Chronic headache/migraine 6 0 100% 0 100%  Mean 5.7 0.4  95% 1 84%

Again referring primarily to Table 2, the method of transdermallyadministering the particular embodiment of the inventive compositionincluded: i) identifying the site of one or more symptoms, typicallypain, and having the subject assess their perceived pain level on ascale ranging from 0 to 10, with 0 being the least amount of pain and 10being the greatest amount of pain (indicated in column three as“Pre-Admin Pain Level”); ii) determining the cutaneous nerve branch(es)or main nerve trunk(s) liable for the one or more symptoms; iii)confirming the liability of the cutaneous nerve branch(es) or main nervetrunk(s) for the one or more symptoms by palpation; and iv)transdermally administering the inventive composition along the nervepathway of the cutaneous nerve branch(es) or main nerve trunk(s) liablefor the one or more symptoms, focusing on areas where the cutaneousnerve branch(es) or main nerve trunk(s) emerge superficially from deeperregions. Generally, the inventive composition was transdermallyadministered for a time period of about sixty seconds. Following, thesubject reassessed their perceived pain level at about five minutesafter the transdermal administration of the inventive composition(indicated in column four as “5 Minutes Post-Admin Pain Level”) andagain at about twenty-four hours after the transdermal administration ofthe inventive composition (indicated in column six as “24 HoursPost-Admin Pain Level”).

Again referring primarily to Table 2, the mean pre-administrationperceived pain level was 5.7/10 whereas the mean five minutespost-administration perceived pain level was 0.4/10, resulting in a mean95% reduction in perceived pain level (each subject's percent reductionin perceived pain level indicated in column five as “Percent Reductionin Pain Level”) in relation to the pre-administration perceived painlevel. The mean twenty-four hour post-administration perceived painlevel was 1/10, resulting in a mean 84% reduction in perceived painlevel (each subject's percent reduction in perceived pain levelindicated in column seven as “Percent Reduction in Pain Level”) inrelation to the pre-administration perceived pain level.

Now referring primarily to Table 3, which evidences the results of amethod of transdermally administering a particular embodiment of theinventive composition to twelve subjects (indicated in column 1 as“Subject Number”) who presented with various pain-related complaints(indicated in column 2 as “Primary Complaint”). As to this particularembodiment, the inventive composition included dextrose in an amount ofabout 20% by weight of the inventive composition, sodium bicarbonate inan amount of about 5% by weight of the inventive composition, andvehicle in an amount of about 75% by weight of the inventivecomposition.

TABLE 3 1 Minute Percent Subject Pre-Admin Post-Admin Reduction inNumber Primary Complaint Pain Level Pain Level Pain Level 1 Abdominalpain 6 1 83% 2 Knee pain 6 1 83% 3 Metacarpal- 6 0.5 92% phalangealjoint pain 4 Carpal tunnel pain 6 0 100%  5 Supraspinatus 10 2 80%tendon pain 6 Wrist rheumatoid 3 3  0% arthritis 7 Lower back pain 9 367% 8 Foot complex 3.4 1.5 56% regional pain syndrome 9 Knee pain 5 0100%  10 Achilles tendon pain 6 1 83% 11 Wrist pain 9 0 100%  12 Lowerback pain 7 1.5 79% Mean 6.4 1.2 77%

Again referring primarily to Table 3, the method of transdermallyadministering the particular embodiment of the inventive compositionincluded: i) identifying the site of one or more symptoms, typicallypain, and having the subject assess their perceived pain level on ascale ranging from 0 to 10, with 0 being the least amount of pain and 10being the greatest amount of pain (indicated in column three as“Pre-Admin Pain Level”); ii) determining the cutaneous nerve branch(es)or main nerve trunk(s) liable for the one or more symptoms; iii)confirming the liability of the cutaneous nerve branch(es) or main nervetrunk(s) for the one or more symptoms by palpation; and iv)transdermally administering the inventive composition along the nervepathway of the cutaneous nerve branch(es) or main nerve trunk(s) liablefor the one or more symptoms, focusing on areas where the cutaneousnerve branch(es) or main nerve trunk(s) emerge superficially from deeperregions. Generally, the inventive composition was transdermallyadministered for a time period of about sixty seconds. Following, thesubject reassessed their perceived pain level at about one minute afterthe transdermal administration of the inventive composition (indicatedin column four as “1 Minute Post-Admin Pain Level”).

Again referring primarily to Table 3, the mean pre-administrationperceived pain level was 6.4/10 whereas the mean one minutepost-administration perceived pain level was 1.2/10, resulting in a mean77% reduction in perceived pain level (each subject's percent reductionin perceived pain level indicated in column five as “Percent Reductionin Pain Level”) relative to the pre-administration perceived pain level.

Now referring primarily to Table 4, which evidences the results of amethod of transdermally administering a particular embodiment of theinventive composition to nine subjects (indicated in column 1 as“Subject Number”) who presented with various pain-related complaints(indicated in column 2 as “Primary Complaint”). As to this particularembodiment, the inventive composition included dextrose in an amount ofabout 20% by weight of the inventive composition, sodium bicarbonate inan amount of about 5% by weight of the inventive composition, andvehicle in an amount of about 75% by weight of the inventivecomposition.

TABLE 4 1 Minute Percent Subject Pre-Admin Post-Admin Reduction inNumber Primary Complaint Pain Level Pain Level Pain Level 1 Neck pain 61  83% 2 Plantar fasciitis 6 0 100% 3 Carpal tunnel pain 6 0 100% 4Plantar fasciitis pain 6 2  67% 5 Bilateral ankle pain 4 0 100% 6 Carpaltunnel pain 4 0 100% 7 Extensor ligament 4 0 100% pain 8 Achilles tendonpain 8 1  88% 9 Knee pain 6 0 100% Mean 5.6 0.4  93%

Again referring primarily to Table 4, the method of transdermallyadministering the particular embodiment of the inventive compositionincluded: i) identifying the site of one or more symptoms, typicallypain, and having the subject assess their perceived pain level on ascale ranging from 0 to 10, with 0 being the least amount of pain and 10being the greatest amount of pain (indicated in column three as“Pre-Admin Pain Level”); ii) determining the cutaneous nerve branch(es)or main nerve trunk(s) liable for the one or more symptoms; iii)confirming the liability of the cutaneous nerve branch(es) or main nervetrunk(s) for the one or more symptoms by palpation; iv) transdermallyadministering the inventive composition along the nerve pathway of thecutaneous nerve branch(es) or main nerve trunk(s) liable for the one ormore symptoms, focusing on areas where the cutaneous nerve branch(es) ormain nerve trunk(s) emerge superficially from deeper regions; and v)administering ultrasound to enhance skin penetration of the inventivecomposition. Generally, the inventive composition was transdermallyadministered for a time period of about sixty seconds and ultrasound wasadministered for a time period of about five minutes. Following, thesubject reassessed their perceived pain level at about one minute afterthe ultrasound administration (indicated in column four as “1 MinutePost-Admin Pain Level”).

Again referring primarily to Table 4, the mean pre-administrationperceived pain level was 5.6/10 whereas the mean one minutepost-administration perceived pain level was 0.4/10, resulting in a mean93% reduction in perceived pain level (each subject's percent reductionin perceived pain level indicated in column five as “Percent Reductionin Pain Level”) relative to the pre-administration perceived pain level.

Now referring primarily to Table 5, which evidences the results of thetransdermal administration of a particular embodiment of the inventivecomposition, a first compound, a second compound, and a third compound(as detailed in column one) to a subject who presented with lower backpain in four distinct regions (a first region, a second region, a thirdregion, and a fourth region) along superior cluneal nerves, as detailedin column two. The inventive composition, first compound, secondcompound, and third compound were transdermally administered to thefirst, second, third, and fourth regions, respectively.

As to this particular embodiment, the inventive composition includeddextrose in an amount of about 20% by weight of the inventivecomposition, sodium bicarbonate in an amount of about 5% by weight ofthe inventive composition, and vehicle in an amount of about 75% byweight of the inventive composition.

The first compound included dextrose in an amount of about 10% by weightof the first compound, tannic acid in an amount of about 2% by weight ofthe first compound, aloe vera in an amount of about 0.75% by weight ofthe first compound, and vehicle in an amount of about 87.25% by weightof the first compound.

The second compound included mannitol in an amount of about 20% byweight of the second compound and vehicle in an amount of about 80% byweight of the second compound.

The third compound included dextrose in an amount of about 20% by weightof the third compound and vehicle in an amount of about 80% by weight ofthe third compound.

TABLE 5 Inventive Percent Percent Composition 5 Minutes Reduction 15Minutes Reduction and Distinct Pre-Admin Post-Admin in Pain Post-Adminin Pain Compounds Region Pain Level Pain Level Level Pain Level LevelInventive First Region 9 1 89% 1 89% Composition First Second Region 105 50% 5 50% Compound Second Third Region 9 4 56% 3 66% Compound ThirdFourth Region 10 3 70% 2 80% Compound

Again referring primarily to Table 5, the method of transdermallyadministering the particular embodiment of the inventive composition andeach of the first, second, and third compounds included: i) identifyingthe first, second, third, and fourth regions of pain symptoms; ii)applying 2.5 kg/cm² of pressure via an algometer to each of the first,second, third, and fourth regions of pain symptoms and having thesubject assess their perceived pain level on a scale ranging from 0 to10, with 0 being the least amount of pain and 10 being the greatestamount of pain (indicated in column three as “Pre-Admin Pain Level”);iii) determining the cutaneous nerve branch(es) or main nerve trunk(s)liable for the pain symptoms in each of the first, second, third, andfourth regions; iv) confirming the liability of the cutaneous nervebranch(es) or main nerve trunk(s) for the pain symptoms in each of thefirst, second, third, and fourth regions by palpation; and v)transdermally administering the inventive composition along the nervepathway liable for the pain symptoms proximate the first region; vi)transdermally administering the first compound along the nerve pathwayliable for the pain symptoms proximate the second region; vii)transdermally administering the second compound along the nerve pathwayliable for the pain symptoms proximate the third region; and viii)transdermally administering the third compound along the nerve pathwayliable for the pain symptoms proximate the fourth region. Generally, theinventive composition and each of the first, second, and third compoundswere transdermally administered for a time period of about sixtyseconds. Following, 2.5 kg/cm² of pressure was applied via an algometerto each of the first, second, third, and fourth regions of pain symptomsat about five minutes after the transdermal administration and thesubject reassessed their perceived pain level (indicated in column fouras “5 Minutes Post-Admin Pain Level”) and again at about fifteen minutesafter the transdermal administration, 2.5 kg/cm² of pressure was appliedvia an algometer to each of the first, second, third, and fourth regionsof pain symptoms and the subject reassessed their perceived pain level(indicated in column six as “15 Minutes Post-Admin Pain Level”).

Again referring primarily to Table 5, regarding the inventivecomposition transdermally administered to the first region, the subjectreported an 89% reduction in perceived pain level at five minutespost-administration (indicated in column five as “5 Minutes Post-AdminPain Level”) in relation to the pre-administration perceived pain leveland an 89% reduction in perceived pain level at fifteen minutespost-administration (indicated in column five as “15 Minutes Post-AdminPain Level”) in relation to the pre-administration perceived pain level.Regarding the first compound transdermally administered to the secondregion, the subject reported a 50% reduction in perceived pain level atfive minutes post-administration (indicated in column five as “5 MinutesPost-Admin Pain Level”) in relation to the pre-administration perceivedpain level and a 50% reduction in perceived pain level at fifteenminutes post-administration (indicated in column five as “15 MinutesPost-Admin Pain Level”) in relation to the pre-administration perceivedpain level. Regarding the third compound transdermally administered tothe third region, the subject reported a 56% reduction in perceived painlevel at five minutes post-administration (indicated in column five as“5 Minutes Post-Admin Pain Level”) in relation to the pre-administrationperceived pain level and a 66% reduction in perceived pain level atfifteen minutes post-administration (indicated in column five as “15Minutes Post-Admin Pain Level”) in relation to the pre-administrationperceived pain level. Regarding the fourth compound transdermallyadministered to the fourth region, the subject reported a 70% reductionin perceived pain level at five minutes post-administration (indicatedin column five as “5 Minutes Post-Admin Pain Level”) in relation to thepre-administration perceived pain level and an 80% reduction inperceived pain level at fifteen minutes post-administration (indicatedin column five as “15 Minutes Post-Admin Pain Level”) in relation to thepre-administration perceived pain level. Overall, of the inventivecomposition, and first, second, and third compounds, the greatestpercent reduction in perceived pain level at both five minutespost-administration and fifteen minutes post-administration was observedfollowing transdermal administration of the inventive composition.

Now referring primarily to Table 6, which evidences the results of thetransdermal administration of a particular embodiment of the inventivecomposition, the first compound, the second compound, and the thirdcompound (as detailed in column one) to a subject who presented withknee pain in four distinct regions (a first region, a second region, athird region, and a fourth region) along cutaneous branches of thefemoral nerve, as detailed in column two. Upon presentation, the subjectwas medicating with oxycodone/acetaminophen (5/325 milligrams every fourto six hours), yet still reported significant perceived pain. Theinventive composition, first compound, second compound, and thirdcompound were transdermally administered to the first, second, third,and fourth regions, respectively.

As to this particular embodiment, the inventive composition includeddextrose in an amount of about 20% by weight of the inventivecomposition, sodium bicarbonate in an amount of about 5% by weight ofthe inventive composition, and vehicle in an amount of about 75% byweight of the inventive composition.

The first compound included dextrose in an amount of about 10% by weightof the first compound, tannic acid in an amount of about 2% by weight ofthe first compound, aloe vera in an amount of about 0.75% by weight ofthe first compound, and vehicle in an amount of about 87.25% by weightof the first compound.

The second compound included mannitol in an amount of about 20% byweight of the second compound and vehicle in an amount of about 80% byweight of the second compound.

The third compound included dextrose in an amount of about 20% by weightof the third compound and vehicle in an amount of about 80% by weight ofthe third compound.

TABLE 6 Inventive Percent Percent Composition 5 Minutes Reduction 15Minutes Reduction and Distinct Pre-Admin Post-Admin in Pain Post-Adminin Pain Compounds Region Pain Level Pain Level Level Pain Level LevelInventive First Region 10 1 90% 0 100%  Composition First Second Region8 4 50% 4 50% Compound Second Third Region 7 2 72% 2 72% Compound ThirdFourth Region 7 1 86% 1 86% Compound

Again referring primarily to Table 6, the method of transdermallyadministering the particular embodiment of the inventive composition andeach of the first, second, and third compounds included: i) identifyingthe first, second, third, and fourth regions of pain symptoms; ii)applying 2.5 kg/cm² of pressure via an algometer to each of the first,second, third, and fourth regions of pain symptoms and having thesubject assess their perceived pain level on a scale ranging from 0 to10, with 0 being the least amount of pain and 10 being the greatestamount of pain (indicated in column three as “Pre-Admin Pain Level”);iii) determining the cutaneous nerve branch(es) or main nerve trunk(s)liable for the pain symptoms in each of the first, second, third, andfourth regions; iv) confirming the liability of the cutaneous nervebranch(es) or main nerve trunk(s) for the pain symptoms in each of thefirst, second, third, and fourth regions by palpation; and v)transdermally administering the inventive composition along the nervepathway liable for the pain symptoms proximate the first region; vi)transdermally administering the first compound along the nerve pathwayliable for the pain symptoms proximate the second region; vii)transdermally administering the second compound along the nerve pathwayliable for the pain symptoms proximate the third region; and viii)transdermally administering the third compound along the nerve pathwayliable for the pain symptoms proximate the fourth region. Generally, theinventive composition and each of the first, second, and third compoundswere transdermally administered for a time period of about sixtyseconds. Following, 2.5 kg/cm² of pressure was applied via an algometerto each of the first, second, third, and fourth regions of pain symptomsat about five minutes after the transdermal administration and thesubject reassessed their perceived pain level (indicated in column fouras “5 Minutes Post-AdminPain Level”) and again at about fifteen minutesafter the transdermal administration, 2.5 kg/cm² of pressure was appliedvia an algometer to each of the first, second, third, and fourth regionsof pain symptoms and the subject reassessed their perceived pain level(indicated in column six as “15 Minutes Post-Admin Pain Level”).

Again referring primarily to Table 6, regarding the inventivecomposition transdermally administered to the first region, the subjectreported a 90% reduction in perceived pain level at five minutespost-administration (indicated in column five as “5 Minutes Post-AdminPain Level”) in relation to the pre-administration perceived pain leveland a 100% reduction in perceived pain level at fifteen minutespost-administration (indicated in column five as “15 Minutes Post-AdminPain Level”) in relation to the pre-administration perceived pain level.Regarding the first compound transdermally administered to the secondregion, the subject reported a 50% reduction in perceived pain level atfive minutes post-administration (indicated in column five as “5 MinutesPost-Admin Pain Level”) in relation to the pre-administration perceivedpain level and a 50% reduction in perceived pain level at fifteenminutes post-administration (indicated in column five as “15 MinutesPost-Admin Pain Level”) in relation to the pre-administration perceivedpain level. Regarding the third compound transdermally administered tothe third region, the subject reported a 72% reduction in perceived painlevel at five minutes post-administration (indicated in column five as“5 Minutes Post-Admin Pain Level”) in relation to the pre-administrationperceived pain level and a 72% reduction in perceived pain level atfifteen minutes post-administration (indicated in column five as “15Minutes Post-Admin Pain Level”) in relation to the pre-administrationperceived pain level. Regarding the fourth compound transdermallyadministered to the fourth region, the subject reported an 86% reductionin perceived pain level at five minutes post-administration (indicatedin column five as “5 Minutes Post-Admin Pain Level”) in relation to thepre-administration perceived pain level and an 86% reduction inperceived pain level at fifteen minutes post-administration (indicatedin column five as “15 Minutes Post-Admin Pain Level”) in relation to thepre-administration perceived pain level. Overall, of the inventivecomposition, and first, second, and third compounds, the greatestpercent reduction in perceived pain level at both five minutespost-administration and fifteen minutes post-administration was observedfollowing transdermal administration of the inventive composition.

Now referring primarily to Table 7, which evidences the results of thetransdermal administration of a first inventive composition, a secondinventive composition, a first compound, and a second compound (asdetailed in column one) to a subject who presented with lower back painin four distinct regions (a first region, a second region, a thirdregion, and a fourth region), as detailed in column two. Uponpresentation, the subject was having a trochanteric shot administeredevery four weeks. In addition, the subject was medicating with a steroidpak, celecoxib (200 milligrams every twenty-four hours), andoxycodone/acetaminophen (10/325 milligrams every four hours), yet stillreported significant perceived pain. The first inventive composition,the second inventive composition, the first compound, and the secondcompound were transdermally administered to the first, second, third,and fourth regions, respectively.

As to this particular embodiment, the first inventive compositionincluded dextrose in an amount of about 25% by weight of the firstinventive composition, sodium bicarbonate in an amount of about 2.5% byweight of the first inventive composition, and vehicle in an amount ofabout 72.5% by weight of the first inventive composition.

The second inventive composition included dextrose in an amount of about20% by weight of the second inventive composition, sodium bicarbonate inan amount of about 10% by weight of the second inventive composition,and vehicle in an amount of about 70% by weight of the second inventivecomposition.

The first compound included sodium bicarbonate in an amount of about2.5% by weight of the first compound and vehicle in an amount of about97.5% by weight of the first compound.

The second compound included mannitol in an amount of about 2.5% byweight of the second compound and vehicle in an amount of about 97.5% byweight of the second compound.

TABLE 7 Inventive Percent Percent Composition 5 Minutes Reduction 15Minutes Reduction and Distinct Pre-Admin Post-Admin in Pain Post-Adminin Pain Compounds Region Pain Level Pain Level Level Pain Level LevelFirst First Region 7 3 57% 3 57% Inventive Composition Second SecondRegion 6 1 83% 1 83% Inventive Composition First Third Region 9 8 11% 722% Compound Second Fourth Region 6 3 50% 3 50% Compound

Again referring primarily to Table 7, the method of transdermallyadministering the particular embodiment of the inventive composition andeach of the first, second, and third compounds included: i) identifyingthe first, second, third, and fourth regions of pain symptoms; ii)applying 2.0 kg/cm² of pressure via an algometer to each of the first,second, third, and fourth regions of pain symptoms and having thesubject assess their perceived pain level on a scale ranging from 0 to10, with 0 being the least amount of pain and 10 being the greatestamount of pain (indicated in column three as “Pre-Admin Pain Level”);iii) determining the cutaneous nerve branch(es) or main nerve trunk(s)liable for the pain symptoms in each of the first, second, third, andfourth regions; iv) confirming the liability of the cutaneous nervebranch(es) or main nerve trunk(s) for the pain symptoms in each of thefirst, second, third, and fourth regions by palpation; and v)transdermally administering the inventive composition along the nervepathway liable for the pain symptoms proximate the first region; vi)transdermally administering the first compound along the nerve pathwayliable for the pain symptoms proximate the second region; vii)transdermally administering the second compound along the nerve pathwayliable for the pain symptoms proximate the third region; and viii)transdermally administering the third compound along the nerve pathwayliable for the pain symptoms proximate the fourth region. Generally,each of the first inventive composition, the second inventivecomposition, the first compound, and the second compound weretransdermally administered for a time period of about sixty seconds.Following, 2.5 kg/cm² of pressure was applied via an algometer to eachof the first, second, third, and fourth regions of pain symptoms atabout five minutes after the transdermal administration and the subjectreassessed their perceived pain level (indicated in column four as “5Minutes Post-Admin Pain Level”) and again at about fifteen minutes afterthe transdermal administration, 2.5 kg/cm² of pressure was applied viaan algometer to each of the first, second, third, and fourth regions ofpain symptoms and the subject reassessed their perceived pain level(indicated in column six as “15 Minutes Post-Admin Pain Level”).

Again referring primarily to Table 7, regarding the first inventivecomposition transdermally administered to the first region, the subjectreported a 57% reduction in perceived pain level at five minutespost-administration (indicated in column five as “5 Minutes Post-AdminPain Level”) in relation to the pre-administration perceived pain leveland a 57% reduction in perceived pain level at fifteen minutespost-administration (indicated in column five as “15 Minutes Post-AdminPain Level”) in relation to the pre-administration perceived pain level.Regarding the second inventive composition transdermally administered tothe second region, the subject reported an 83% reduction in perceivedpain level at five minutes post-administration (indicated in column fiveas “5 Minutes Post-Admin Pain Level”) in relation to thepre-administration perceived pain level and an 83% reduction inperceived pain level at fifteen minutes post-administration (indicatedin column five as “15 Minutes Post-Admin Pain Level”) in relation to thepre-administration perceived pain level. Regarding the first compoundtransdermally administered to the third region, the subject reported an11% reduction in perceived pain level at five minutespost-administration (indicated in column five as “5 Minutes Post-AdminPain Level”) in relation to the pre-administration perceived pain leveland a 22% reduction in perceived pain level at fifteen minutespost-administration (indicated in column five as “15 MinutesPost-AdminPain Level”) in relation to the pre-administration perceivedpain level. Regarding the second compound transdermally administered tothe fourth region, the subject reported a 50% reduction in perceivedpain level at five minutes post-administration (indicated in column fiveas “5 Minutes Post-Admin Pain Level”) in relation to thepre-administration perceived pain level and a 50% reduction in perceivedpain level at fifteen minutes post-administration (indicated in columnfive as “15 Minutes Post-Admin Pain Level”) in relation to thepre-administration perceived pain level. Overall, of the first inventivecomposition, the second inventive composition, the first compound, andthe second compound, the greater percent reduction in perceived painlevel at both five minutes post-administration and fifteen minutespost-administration was observed following transdermal administration ofthe first and second inventive compositions, with the greatest percentreduction in perceived pain level at both five minutespost-administration and fifteen minutes post-administration observedfollowing transdermal administration of the second inventivecomposition.

A method of producing a particular embodiment of the inventivecomposition can include combining an amount of sugar or sugar alcohol,an amount of alkalizing agent, and an amount of vehicle; and formulatingthe inventive composition for transdermal administration.

As used herein, the term “combination or combining” refers to any methodof putting two or more materials together. Such methods include, but arenot limited to, mixing, blending, commingling, concocting, homogenizing,ultrasonic homogenizing, incorporating, intermingling, fusing, joining,shuffling, stirring, coalescing, integrating, confounding, joining,uniting, creating a stable suspension of two immiscible liquids via anynumber of means such as emulsions, or the like.

As to particular embodiments, the method of producing a particularembodiment of the inventive composition can include combining the sugaror sugar alcohol, alkalizing agent, and vehicle, whereby each can becombined in an amount as described above.

As to particular embodiments, the method of producing a particularembodiment of the inventive composition can further include combiningone or more additional components to formulate the inventivecomposition, whereby the one or more additional components can be asdescribed above or can be other additional components.

As can be easily understood from the foregoing, the basic concepts ofthe present invention may be embodied in a variety of ways. Theinvention involves numerous and varied embodiments of a pain relievingsystem and methods for making and using such pain relieving systemsincluding the best mode.

As such, the particular embodiments or elements of the inventiondisclosed by the description or shown in the figures or tablesaccompanying this application are not intended to be limiting, butrather exemplary of the numerous and varied embodiments genericallyencompassed by the invention or equivalents encompassed with respect toany particular element thereof. In addition, the specific description ofa single embodiment or element of the invention may not explicitlydescribe all embodiments or elements possible; many alternatives areimplicitly disclosed by the description and figures.

It should be understood that each element of an apparatus or each stepof a method may be described by an apparatus term or method term. Suchterms can be substituted where desired to make explicit the implicitlybroad coverage to which this invention is entitled. As but one example,it should be understood that all steps of a method may be disclosed asan action, a means for taking that action, or as an element which causesthat action. Similarly, each element of an apparatus may be disclosed asthe physical element or the action which that physical elementfacilitates. As but one example, the disclosure of a “combination”should be understood to encompass disclosure of the act of“combining”—whether explicitly discussed or not—and, conversely, werethere effectively disclosure of the act of “combining”, such adisclosure should be understood to encompass disclosure of a“combination” and even a “means for combining”. Such alternative termsfor each element or step are to be understood to be explicitly includedin the description.

In addition, as to each term used it should be understood that unlessits utilization in this application is inconsistent with suchinterpretation, common dictionary definitions should be understood toincluded in the description for each term as contained in the RandomHouse Webster's Unabridged Dictionary, second edition, each definitionhereby incorporated by reference.

All numeric values herein are assumed to be modified by the term“about”, whether or not explicitly indicated. For the purposes of thepresent invention, ranges may be expressed as from “about” oneparticular value to “about” another particular value. When such a rangeis expressed, another embodiment includes from the one particular valueto the other particular value. The recitation of numerical ranges byendpoints includes all the numeric values subsumed within that range. Anumerical range of one to five includes for example the numeric values1, 1.5, 2, 2.75, 3, 3.80, 4, 5, and so forth. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. When a value is expressed as an approximation by use of theantecedent “about,” it will be understood that the particular valueforms another embodiment. The term “about” generally refers to a rangeof numeric values that one of skill in the art would consider equivalentto the recited numeric value or having the same function or result.Similarly, the antecedent “substantially” means largely, but not wholly,the same form, manner or degree and the particular element will have arange of configurations as a person of ordinary skill in the art wouldconsider as having the same function or result. When a particularelement is expressed as an approximation by use of the antecedent“substantially,” it will be understood that the particular element formsanother embodiment.

Moreover, for the purposes of the present invention, the term “a” or“an” entity refers to one or more of that entity unless otherwiselimited. As such, the terms “a” or “an”, “one or more” and “at leastone” can be used interchangeably herein.

Thus, the applicant(s) should be understood to claim at least: i) eachof the pain relieving systems herein disclosed and described, ii) therelated methods disclosed and described, iii) similar, equivalent, andeven implicit variations of each of these devices and methods, iv) thosealternative embodiments which accomplish each of the functions shown,disclosed, or described, v) those alternative designs and methods whichaccomplish each of the functions shown as are implicit to accomplishthat which is disclosed and described, vi) each feature, component, andstep shown as separate and independent inventions, vii) the applicationsenhanced by the various systems or components disclosed, viii) theresulting products produced by such systems or components, ix) methodsand apparatuses substantially as described hereinbefore and withreference to any of the accompanying examples, x) the variouscombinations and permutations of each of the previous elementsdisclosed.

The background section of this patent application provides a statementof the field of endeavor to which the invention pertains. This sectionmay also incorporate or contain paraphrasing of certain United Statespatents, patent applications, publications, or subject matter of theclaimed invention useful in relating information, problems, or concernsabout the state of technology to which the invention is drawn toward. Itis not intended that any United States patent, patent application,publication, statement or other information cited or incorporated hereinbe interpreted, construed or deemed to be admitted as prior art withrespect to the invention.

The claims set forth in this specification, if any, are herebyincorporated by reference as part of this description of the invention,and the applicant expressly reserves the right to use all of or aportion of such incorporated content of such claims as additionaldescription to support any of or all of the claims or any element orcomponent thereof, and the applicant further expressly reserves theright to move any portion of or all of the incorporated content of suchclaims or any element or component thereof from the description into theclaims or vice-versa as necessary to define the matter for whichprotection is sought by this application or by any subsequentapplication or continuation, division, or continuation-in-partapplication thereof, or to obtain any benefit of, reduction in feespursuant to, or to comply with the patent laws, rules, or regulations ofany country or treaty, and such content incorporated by reference shallsurvive during the entire pendency of this application including anysubsequent continuation, division, or continuation-in-part applicationthereof or any reissue or extension thereon.

Additionally, the claims set forth in this specification, if any, arefurther intended to describe the metes and bounds of a limited number ofthe preferred embodiments of the invention and are not to be construedas the broadest embodiment of the invention or a complete listing ofembodiments of the invention that may be claimed. The applicant does notwaive any right to develop further claims based upon the description setforth above as a part of any continuation, division, orcontinuation-in-part, or similar application.

1-60. (canceled)
 61. A method for relieving pain, comprising:transdermally administering a composition along a nerve pathway of anerve, said composition comprising pain relievers consisting of: (i) anamount of sugar or sugar alcohol; and (ii) an amount of alkalizingagent; wherein transdermal administration of said composition iseffective to decrease neurogenic pain associated with said nerve. 62.The method of claim 61, wherein said amount of sugar or sugar alcohol isbetween 5% to 30% by weight of said composition.
 63. The method of claim61, wherein said amount of alkalizing agent is between 5% to 15% byweight of said composition.
 64. The method of claim 63, wherein saidalkalizing agent is sodium bicarbonate.
 65. The method of claim 61,further comprising transdermally administering said compositionformulated as a fluid selected from the group consisting of: lotion,cream, emulsion, ointment, gel, foam, paste, oil, lipid delivery system,spray, and drops.
 66. A method for relieving pain, comprising:transdermally administering a composition along a nerve pathway of anerve, said composition comprising pain relievers consisting of anamount of sugar or sugar alcohol; wherein transdermal administration ofsaid composition is effective to decrease neurogenic pain associatedwith said nerve.
 67. The method of claim 66, wherein said amount ofsugar or sugar alcohol is between 5% to 30% by weight of saidcomposition.
 68. The method of claim 66, wherein said amount ofalkalizing agent is between 5% to 15% by weight of said composition. 69.The method of claim 68, wherein said alkalizing agent is sodiumbicarbonate.
 70. The method of claim 66, further comprisingtransdermally administering said composition formulated as a fluidselected from the group consisting of: lotion, cream, emulsion,ointment, gel, foam, paste, oil, lipid delivery system, spray, anddrops.
 71. A composition for relieving pain, comprising: pain relieversconsisting of: (i) an amount of sugar or sugar alcohol; and (ii) anamount of alkalizing agent; wherein transdermal administration of saidcomposition along a nerve pathway of a nerve is effective to decreaseneurogenic pain associated with said nerve.
 72. The composition of claim71, wherein said amount of sugar or sugar alcohol is between 5% to 30%by weight of said composition.
 73. The composition of claim 71, whereinsaid amount of alkalizing agent is between 5% to 15% by weight of saidcomposition.
 74. The composition of claim 73, wherein said alkalizingagent is sodium bicarbonate.
 75. The composition of claim 71, whereinsaid composition is formulated as a fluid selected from the groupconsisting of: lotion, cream, emulsion, ointment, gel, foam, paste, oil,lipid delivery system, spray, and drops.
 76. A composition for relievingpain, comprising: pain relievers consisting of an amount of sugar orsugar alcohol; wherein transdermal administration of said compositionalong a nerve pathway of a nerve is effective to decrease neurogenicpain associated with said nerve.
 77. The composition of claim 76,wherein said amount of sugar or sugar alcohol is between 5% to 30% byweight of said composition.
 78. The composition of claim 76, whereinsaid amount of alkalizing agent is between 5% to 15% by weight of saidcomposition.
 79. The composition of claim 78, wherein said alkalizingagent is sodium bicarbonate.
 80. The composition of claim 76, whereinsaid composition is formulated as a fluid selected from the groupconsisting of: lotion, cream, emulsion, ointment, gel, foam, paste, oil,lipid delivery system, spray, and drops.